The present invention relates to novel methods of using known pharmacological agents. Particularly, the present invention relates to the use of certain prostaglandins in the treatment and prevention of bone diseases (particularly metabolic bone diseases, e.g., osteoporoses), and the treatment and prevention of joint and dental diseases in both humans and animals. This invention also relates to the use of these known pharmacological agents to increase the rate of bone healing in conditions of fractures, bone grafts and the like.
Medical research has found, in recent years, that most metabolic bone diseases (especially those in adults, e.g., osteoporosis proper) result from derangements of mechanisms governing the bone turnover processes (bone modeling and/or remodeling). These bone turnover processes contribute to the establishment of and subsequent maintainence of the mechanical competence of the skeleton. These processes operate by the coupled and coordinated activity of two continually renewing cell populations, and are initiated following some stimulus or "activation" that causes the proliferation and differentiation of these cells. These cells are osteoblasts and osteoclasts which have complimentary but directionally opposite activity. Osteoblasts are the cells which carry out the function of bone formation, and function in the healthy vertebrate together with osteoclasts, cells that function in the resorption and removal of bone.
The defective mechanisms of bone turnover leading to osteoporoses differ in the young and the adult. Growth and modeling are generally affected in the young, and remodeling (and modeling to some degree) are affected in the adult. Also, the young experience a defect in the expected accumulation of bone tissue, whereas an excessive loss of bone tissue is observed in the adult. Subnormal accumulation of bone tissue during growth, remaining asymptomatic during youth, can predispose an adult to develop osteoporosis or osteopenia.
The following definitions will be helpful in the understanding of this invention:
(a) "Osteopenia" is that skeletal condition of mammals characterized by a decreased volume of mineralized bone tissue.
(b) "Irreversible osteopenia" (osteoporosis) is that skeletal condition characterized by a reduction in total bone volume. (Distinguishing between total and mineralized bone volumes is thus important in the diagnosis of the disorder and its pathogenisis, and to assess the efficacy of treatment. See, e.g., Z. F. G. Jaworski, "Physiology and Pathology of Bone Remodeling," in Symposium on Osteoporosis in the Orthopedic Clinics of North America Vol. 12 (1981).)
(c) "Longitudinal Growth" refers to the enlargement of bone in length by the endochondral ossification process.
(d) "Appositional Growth" refers to that growth process which, when it acts alone (as observed in those skeletons following paralysis and diseases of congenital origin) causes uniform increases in all cross-sectional diameters and results in a basically circular diaphyseal cross section.
(e) "Modeling" refers to the process of bone activation followed by resorption at one bone site with a simultaneous activation of bone formation at another bone site. The modeling process accelerates certain diameters over others in response to biomechanical demands acting upon them. The modeling activity results in irregular cross sections with varying cortical thickness, as well as gross longitudinal curvatures of whole bone such as one finds normally in the clavicle, rib, radius, etc.
(f) "Remodeling" refers to the process of bone activation followed by resorption and then new bone formation at the same bone site in temporal sequence. The remodeling process results in modest changes in the relative amounts of bone resorbed and replaced on periosteal surfaces and causes a continued but slow expansion of the periosteal envelope throughout adult life.
Osteoporosis is a condition common in animals and particularly adult humans and typically results in a decrease in bone volume of both the bone matrix (the substrate, collagen), and the bone mineral, Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 or "hydroxyapatite". Osteoporosis typically results in numerous symptomatic manifestations, including back pain, femoral neck fractures, Colles fractures, and deformation of the back bone. The bones of the afflicted animal may also become brittle, which increases the likelihood and incidences of fractures. Various types of osteoporosis are known. See for example The Merck Manual, 13th Edition, 1365-1366 (1977) and Dorland's Illustrated Medical Dictionary, 24th Edition. W. B. Saunders Company, London (1965).
Osteoporosis may be classified in many ways. One method of classification is by occurrence in life. Under this classification system, there exist osteoporoses of the following types:
1. Congenital, wherein the animal is born with a basic inability to accumulate bony tissue as rapidly and in the amounts necessary to meet the mechanical demands imposed on the skeleton. An example of this condition is called Osteogenesis Imperfecta.
2. Growth-related, wherein the animal during immaturity suffers from some condition which causes the growing skeleton to accumulate less bone than a normal growing skeleton and results in a individual with less than the normal amount of bone tissue. There is an alteration in bone formation, resorption, growth, modeling and remodeling processes. These osteoporoses are usually characterized by nearly normal periosteal diameters at midshaft relative to their lengths, but relatively enlarged marrow cavity and less than the normal steepness of metophyseal inflaring. Examples of this type of osteoporosis include biliary stenosis, eunuchism, arthrogryphosis (following paralysis due to poliomyelitis), muscular dystrophy, and certain osteoporoses which are secondary to a pre-existing hematopoietic disease, which conditions pathogenically resemble those of acquired osteoporosis (discussed infra) but occur in an immature skeleton.
3. Acquired osteoporoses, both symptomatic and asymptomatic, may be classified into a number of types, whose etiology is not well understood. Examples of this type of osteoporosis include senile osteoporosis, post menopausal osteoporosis, Cushing's Osteoporosis, Mast Cell Disease, Thyrotoxicosis, Primary Hyperparathyroidisim, True Disuse Osteoporosis, Post Traumatic Osteodystrophy and Burned-out Acromegaly.
Another method of classifying osteoporoses is by the change in bone dynamics. Under this classification, there exist the following classifications:
1. Osteoporoses characterized by decreased bone turnover rate--this includes decreased activation, resorption, and formation rates. Examples of this type of osteoporosis include senile osteoporosis; post menopausal osteoporosis, Cushing's Osteoporosis; Muscular Dystrophy; True Disuse Osteoporosis; Burned-out Acromegaly; Chronic Renal failure; and estrogen therapy. The first five osteoporoses are not reversed naturally, and affect primarily the endosteal surfaces. Burned-out Acromegaly is also not reversed naturally and affects primarily the endosteal and periosteal surfaces. Classic renal failure is not reversed naturally and little is known about estrogen therapy. There is no known or proven cure for any of these osteoporoses, and data on estrogenic therapy is not complete.
2. Osteoporoses characterized by increased bone-turnover rate: examples of these kinds of osteoporoses include thyrotoxicosis (which is reversible via surgery and affects primarily periosteal, haversian, and endosteal surfaces; certain kinds of osteogenesis imperfecta, which is not reversed naturally and affects primarily periosteal and endosteal surfaces; and post traumatic osteodystrophy, which is naturally reversable and effects primarily the periosteal, haversian, and endosteal surfaces.
3. Normal or variable bone-turnover rate: examples of this condition include mass cell disease (and similar conditions including neoplasia); Eunuchism; and Primary Hyperparathyroidism. The first two conditions are not reversed naturally and affect primarily the endosteal surface. Primary Hyperparathyroidism affects primarily the periosteal, haversian, and endosteal surfaces. The reversability of these conditions varies.
The method of the present invention should be useful in treating the conditions of bone dynamics described under 1 and 3 above.
Factors which affect bone-turnover include:
1. Endocrine factors: mesenchymal cell activation and thus remodeling rates are consistently increased in acromegaly and Thyrotoxicosis while they are decreased in Cushing's disease and analogous syndromes involving anti-inflammatory steroid therapy; oophorectomy; menopause; and the like.
2. Vascular factors: regional large increases in bone remodeling follows local tissue injury and consistently and proportionally is associated with increased tissue perfusion by the blood. The local tissue injury may consist of a fracture, a burn to overlying skin, obvious injury to underlying deep tissue, a surgical procedure of bone or soft tissue, local infections, etc.
3. Neurological factors: a transient increase in regional remodeling regularly occurs following trauma to, infection of, or transection of major peripheral nerves supplying the region; individuals suffering from poliomyeditis have consistently symmetrically circular cortices due to the lack of significant modeling activity and functional innervation.
4. Age Factors: bone turnover proceeds at a greater rate and frequency in the young compared to the adult. In some adult skeletons bone turnover may be only trivial resulting in significant clinical disease.
5. Mechanical factors: mechanical loading apparently directly stimulates skeletal turnover by manipulating microenvironmental factors of bone surfaces e.g. space travel for prolonged periods associated with reduced gravitational forces, prolonged bed rest, and the like.
6. Interceptive, repairative, and/or corrective surgical procedures involving diseased, deformed, and/or transplanted mineralized tissue;
7. Primary and/or Secondary Nutritional Factors (e.g., primary biliary and alcoholic cirrhosis); and
8. Renal dialysis.
A primary goal of osteoporosis therapy is to increase bone tissue mass by increasing bone formation and/or decreasing bone resorption.
The prostaglandins used in the present invention are derivatives of prostanoic acid. A trivial system of nomenclature has been devised, which classifies the prostaglandins according to the substituents on the cyclopentane ring. See, N. A. Nelson, Journal of Medicinal Chemistry, 17:911 (1974). For a further discussion of the prostaglandins, see Bergstrom, et al., Pharmacol. Rev. 20:1 (1968), and references cited therein.
The term prostaglandin analog herein refers to those compounds structurally related to the prostaglandins (in that they exhibit a cyclopentane, or adjacently homologous cycloalkane, ring and a pair of side chains attached to adjacent carbon atoms of the ring) which retain characteristic biological properties of the prostaglandins. See Bergstom, cited above. Various structural modifications of the prostaglandins are known to produce useful prostaglandin analogs. Many of these structural modifications are discussed in the U.S. patents set forth below.